This invention relates to a process for the production of the antibiotic of formula (A), ##STR1## where R is any group which gives a compound having antibacterial activity and X is hydrogen or a pharmaceutically acceptable cation and Y is a pharmaceutically acceptable cation.
A subgroup of compounds of formula A (one is sold commercially under the name "Monocid") are disclosed in two U.S. Pat. Nos. 4,048,311 and 4,576,937. The mono-sodium salt of the sulfomethyl group is specifically described and claimed in the later '937 patent. The antibacterial activity of these compounds is described in U.S. Pat. No. 4,048,311 (see column 6, line 19 to column 9, line 49 and the data in Tables 1 and 2).
The '937 patent discloses a chemical synthesis for certain of the compounds of formula A, particularly the salts such as the sodium salt. That process comprises reacting a compound of formula (B) ##STR2## with inter alia O-formylmandelic acid to produce a formyl intermediate of formula (C). ##STR3## Alkali hydrolyzes the --OCHO group giving the corresponding alcohol of formula (D), ##STR4## a compound called cefonicid sodium where X and Y are sodium, in 80 to 85% yield. The decreased product yield is possibly due to the degradation of both the formyl intermediate (C) and cefonicid sodium by alkali. Hydrolysis at neutral or mildly acidic conditions increases the stability of (C) and the resulting cefonicid salt but decreases the hydrolysis rate significantly. An alternative more efficient procedure was needed.
Hydrolases such as lipases, esterases, and amidases are employed in the stereospecific and regiospecific hydrolyses of ester and amide linkages. The biological function of lipases is to catalyze the hydrolysis of triacylglycerol to the corresponding fatty acid precursors and glycerol. Lipases are not known to hydrolyze an ester linkage which is part of a cephalosporin nucleus as in (C). Esterases hydrolyze soluble carboxylic acid esters to the corresponding acid and alcohol precursors. Esterases from Escliericliia coli, Pseudomonas aeruginosa, Aspergillus niger and Saccharomyces sp. hydrolyze ester linkages (U.S. Pat. No. 4,346,168) in which the carboxyl group is bonded to a penicillin of the formula (E), ##STR5## where R.sup.x is an alkyl, aryl, or arylalkyl group.
However, (C) is structurally different from (E). The current knowledge of lipases and esterases does not predict that any of these enzymes will be able to hydrolyze the formyl intermediate of the cephalosporins of this invention as illustrated by formula (C).
The object of the work leading to this invention was to find out whether a hydrolase-dependent enzymatic process would transform the formyl intermediate (C), or another such cephalosporin ester, to cefonicid sodium in quantitative yield in the pH range of about 3.5-8.0.